Fabrazyme (Page 3 of 6)

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other agalsidase products may be misleading.

The following data reflect the percentage of patients whose test results were considered positive for antibodies to Fabrazyme using an ELISA and radioimmunoprecipitation (RIP) assay for antibodies.

Ninety-five of 121 (79%) adult patients and 11 of 16 (69%) pediatric patients (106 of 137, 74% of all patients) treated with Fabrazyme in clinical studies have developed IgG antibodies to Fabrazyme. Most patients who develop IgG antibodies do so within the first three months of exposure. IgG seroconversion in pediatric patients was associated with prolonged half-life of Fabrazyme, a phenomenon rarely observed in adult patients [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.4)]. A possible cause for this prolongation likely pertains to the ability of antibodies to act as “carriers” for their antigens. Among the 14 female patients exposed to Fabrazyme in clinical studies, six (adult patients) developed IgG antibodies to Fabrazyme.

IgG antibodies to Fabrazyme were purified from 15 patients with high antibody titers (≥12,800) and studied for inhibition of in vitro enzyme activity. Under the conditions of this assay, most of these 15 patients had inhibition of in vitro enzyme activity ranging between 21%–74% at one or more time points during the study. Assessment of inhibition of enzyme uptake in cells has not been performed. No general pattern was seen in individual patient reactivity over time. The clinical significance of binding and/or inhibitory antibodies to Fabrazyme is not known. In patients followed in the open-label extension study, reduction of GL-3 in plasma and GL-3 inclusions in superficial skin capillaries was maintained after antibody formation.

Testing for IgE antibodies was performed in approximately 60 patients in clinical trials who experienced moderate to severe infusion-associated reactions or in whom mast cell activation was suspected. Seven of these patients tested positive for Fabrazyme-specific IgE antibodies or had a positive skin test to Fabrazyme. Patients who have had a positive skin test to Fabrazyme, or who have tested positive for Fabrazyme-specific IgE antibodies in clinical trials with Fabrazyme have been rechallenged [see Clinical Studies (14), Warnings and Precautions (5.4), and Dosage and Administration (2.1)].

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Fabrazyme. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Cardiovascular: cardiorespiratory arrest, cardiac failure, myocardial infarction, palpitations,
  • Infections: sepsis and pneumonia
  • Infusion-associated reactions: anaphylaxis [see Warnings and Precautions (5.1)] , localized angioedema (including auricular swelling, eye swelling, dysphagia, lip swelling, edema, pharyngeal edema, face swelling, and swollen tongue), and bronchospasm
  • General: hyperhidrosis, asthenia, infusion site reaction
  • Lymphatic: lymphadenopathy
  • Musculoskeletal: arthralgia
  • Nasopharyngeal: rhinorrhea
  • Neurologic: cerebrovascular accident, hypoesthesia, oral hypoesthesia
  • Ophthalmologic: increased lacrimation
  • Pulmonary: respiratory failure, hypoxia
  • Renal: renal failure
  • Dermatologic: erythema
  • Vascular: leukocytoclastic vasculitis

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

Pregnant women and women of reproductive potential should be encouraged to enroll in the Fabry patient registry. The registry will monitor the effect of Fabrazyme on pregnant women and their offspring. For more information, visit www.registrynxt.com or call 1-800-745-4447, extension 15500.

Risk Summary

Available data from postmarketing case reports and case series with Fabrazyme use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Reproduction studies performed in rats at doses up to 68 times the human dose have revealed no evidence of effects on embryo-fetal development (see Data).

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal data

The effects of agalsidase beta on embryo-fetal development in rats were evaluated at doses of 3, 10, and 30 mg/kg/day (up to 68 times the human dose of 1 mg/kg every 2 weeks on a body surface area basis) during gestation days 7 to 17. Hepatocellular necrosis consistent with accumulation of test article was evident in maternal livers in the 10 and 30 mg/kg/day groups (23 and 68 times the human dose on a body surface area basis). There were no adverse effects of agalsidase beta on embryo-fetal development in rats.

8.2 Lactation

Risk Summary

There are no data on the presence of agalsidase beta in either human or animal milk, the effects of the drug on the breastfed infant, or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fabrazyme and any potential adverse effects on the breastfed child from Fabrazyme or from the underlying maternal condition.

Lactating women with Fabry disease treated with Fabrazyme should be encouraged to enroll in the Fabry registry [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of Fabrazyme have been established in pediatric patients 8 years of age and older. Use of Fabrazyme in this age group is supported by evidence from a multinational, multicenter, uncontrolled, open-label study in 16 pediatric patients with Fabry disease (14 males, 2 females) ages 8 to 16 years [see Clinical Studies (14)].

The safety and effectiveness of Fabrazyme have not been established in pediatric patients less than 8 years of age.

8.5 Geriatric Use

Clinical studies of Fabrazyme did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Responses in Women

Fabry disease is an X-linked genetic disorder. However, some heterozygous women will develop signs and symptoms of Fabry disease due to the variability of the X-chromosome inactivation within cells.

A total of 12 adult female patients with Fabry disease were enrolled in two separate randomized, double-blind, placebo-controlled clinical studies with Fabrazyme, and two female pediatric patients with Fabry disease, ages 11 years, were evaluated in an open-label, uncontrolled pediatric study [see Use in Specific Populations (8.4) and Clinical Studies (14)]. Although the safety and efficacy data available in female patients in these clinical studies are limited, there is no indication that female patients respond differently to Fabrazyme compared to males.

10 OVERDOSAGE

There have been no reports of overdose with Fabrazyme. In clinical trials, patients received doses up to 3 mg/kg body weight. The adverse reactions experienced by patients who received treatment with 3 mg/kg were similar to the adverse reactions experienced by patients who received treatment with 1 mg/kg.

11 DESCRIPTION

Agalsidase beta is a recombinant human α-galactosidase A enzyme with the same amino acid sequence as the native enzyme. Purified agalsidase beta is a homodimeric glycoprotein with a molecular weight of approximately 100 kD. The mature protein is comprised of two subunits of 398 amino acids (approximately 51 kD), each of which contains three N-linked glycosylation sites. α-galactosidase A catalyzes the hydrolysis of globotriaosylceramide (GL-3) and other α-galactyl-terminated neutral glycosphingolipids, such as galabiosylceramide and blood group B substances to ceramide dihexoside and galactose. The specific activity of agalsidase beta is approximately 70 U/mg (one unit is defined as the amount of activity that results in the hydrolysis of 1 µmole of a synthetic substrate, p-nitrophenyl-α-D-galactopyranoside, per minute under the assay conditions).

Agalsidase beta is produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system.

Fabrazyme (agalsidase beta) for injection is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, preservative-free, white to off-white, lyophilized cake or powder for reconstitution with Sterile Water for Injection, USP. Each 35 mg vial contains 37 mg of agalsidase beta, as well as 222 mg mannitol, 20.4 mg sodium phosphate monobasic monohydrate, and 59.2 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 35 mg of agalsidase beta (7 mL) may be extracted from each 35 mg vial.

Each 5 mg vial contains 5.5 mg of agalsidase beta, as well as 33.0 mg mannitol, 3.0 mg sodium phosphate monobasic monohydrate, and 8.8 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 5 mg of agalsidase beta (1 mL) may be extracted from each 5 mg vial.

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